PT87077B - METHOD OF PREPARATION OF PHARMACEUTICAL COMPOSITIONS BASED ON BIPRANOLE - Google Patents

Abstract

Pharmaceuticals containing the compound or its salts with acids are used as antiarrhythmics.

Description

French patent 1 494 749 describes derivatives

2-hydroxydiphenyl which are etherified in the phenolic hydroxy group with a 2-hydroxy-3-alkylaminopropyl group. Example 5 describes the structure, as well as the preparation process, of tert-butylamino-3- (phenyl-2'-phenoxy) -1-propanol-2 and its hydrochloride.

It is assumed that these compounds are (5-sympatholytic,

i.e. receptor blockers (¾. Neither pharmacological nor xoxicological data are disclosed in this document.

Surprisingly the formula tert-butylamino-3- (phenyl-2-phenoxy) -1-propanol-2 (bipranole)

and its acid addition salts have been shown to have no {δ-sympatholytic activity, but on the other hand have a potent antiarrhythmic activity.

The electrophysiological and hemodynamic effects were investigated in vitro and in vivo. The results of pharmacological tests using two isolated myocardial preparations, with propafenone diprafenone / and bipranole are shown in Table I.

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-3 TABLE I

Preparation Variation factor Pap maximal muscle of V _max of guinea pig home fiber

Dog Purkinje C20APD95 (yiAM) F.S. Diprafenone 1.19 failed 4.86 Propafenone 1.08 failed 1.55 Bipranole 5 7.2 9.09 C20V: Concentration that reduces V _m „ _v max * max 20% at a length of cycle basic 1000 msec. C20CF: Concentration that reduces contractions of the papillary muscle home to 20%.

Factor variation of ^v max ^; (V _max% control at a basic cycle length of 2000 msec) / (% V _max i a control length. Basic cesium 500 msec) to C20V _raax.

C20APD95: Concentration that increases APD95 of the normal action potential by 20 $.

F.á .: Safety factor, quantified as the variation factor of V _max x (C20CF / C20 V _max ).

The high safety factor of bipranole in relation to diprafenone and propafenone, as well as the high factor of variation of ^v max, are notable. 9 high factor of variation of ^v max indicates that the effectiveness of the compound increases with heart rate. The C20APD95 value indicates that the action potential is increased by 20% in the presence of Lipranole 7.20, a high safety factor indicates that bipranole has no significant negative inotropic side effects, 6m compared both diprafenone and propafenone exhibit inotropic side effects negative, pronounced. Thus, cypranole

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and its acid addition salts, contrary to these prior art compounds, can be used very safely in the treatment of cardiac arrhythmias, especially when the risk of heart failure is high. The results were confirmed by the following in vivo experiments.

The antiarrhythmic effects of the compounds were also tested in dogs, according to the method of H. Olucker et al., DrugRes., 35 (11), 9, (1985). pp. 1387-1393. k left coronary artery was obstructed for more than 2 hours. These compounds were administered intravenously to animals with constant ventricular arrhythmias, a dose of 1.6 mg / kg followed by 50 µg / kg / minute of bipranole reduces ventricular extrasystoles by more than 90%. This represents a considerably lower therapeutic dose than that required with flecainide (2.4 mg / kg followed by 50 µg / kg / minute) currently considered to be one of the most effective antiarrhythmic agents used. Within the therapeutic range (0.2 to 6.4 mg / kg), bipranole does not exhibit cardiodepressive or hemodynamic side effects, or does minimally, which indicates that bipranole has no properties (Ó-sympatholytics,

The parameters used to determine (¾-blocking activity in the anesthetized dog were dP / dt, as a measure of heart contractility and cardiac output. Bipranole showed a positive inotropic effect at doses up to 3 mg / xg and showed no inotropic action. negative up to 30 mg / kg. This is in contrast to the (Ò-oloqueants which have always had negative inocropic effects. The cardiac output was not affected by bipranole at doses up to 30 mg / kg. All amines died at the highest dose (30 mg / kg iv) Thus, the effects observed with this dose are related to non-specific toxic actions and not due to any blockade / 3.

In in vitro experiments. using isolated myocardial preparations, the antiarrhythmic dose (^ 20V _χ ) was oipranoie 2.2yNI. This dose produces the same antiarrhythmic effect as 3 mg / kg (iv) in dogs.

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In the atrial muscle of the guinea pig isolated, the bipranole in the highest test concentration (30 produced a slight reduction in the positive inotropic effect of lyitM adrenaline. This concentration is approximately 14 times higher than that required for an antiarrhythmic effect. As previously mentioned, such high concentrations are in the range that produces toxicity in dogs, k slight reduction observed in the positive inotropic effect, induced by adrenaline lyui is not consequently, due to a sympatholytic effect but to a non-specific toxic action.

This surprisingly large antiarrhythmic effect is not accompanied by a significant increase in toxicity, as can be seen from the comparison of the values in rats, which are summarized in Table II.

Table II

LD

Pro papphenone-HO1

Bipranole-hOl (mg / kg)

Rat (iv) Rat (oral)

18.8

760

571

The previous results suggest that bipranole and its acid addition salts, such as propafenone, may be very useful, clinically, in the treatment of cardiac arrhythmias. However, unlike propafenone, which has potent negative, hypotensive and inotropic side effects, bipranole exhibits little or no negative or hemodynamic inotropic side effects.

bipranole can be prepared according to the method described in French patent 1,494,749 from o- (epoxy -2,3-propoxy) -diphenyl and tert-butylamine.

bipranole is optionally converted to an acid addition salt by means of a pharmacologically acceptable acid, organic or inorganic. There are examples of suitable acids

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ο hydrochloric acid, ο hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, acid adipic acid and benzoic acid. The salts are conventionally obtained by mixing the free base, or its solutions, with the corresponding acid, or their solutions in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, or a lower ketone, such as such as acetone, methyl ethyl ketone or methyl isobutyl ketone or an ether such as diethyl ether, tetrahydrofuran or dioxane. 'lick if you can use mixtures of sun mentioned for better crystal deposition. In addition, aqueous solutions of bipranole salts, which are pharmacologically acceptable, can be prepared by dissolving the free base in an aqueous solution of an acid.

bipranole and its acid addition salts can be administered orally or intravenously. The dosage depends on the age, condition and weight of the patient, as well as the form of administration. Generally, the daily dosage will vary from approximately 5 to 75 mg / kg of body weight, for oral administration, and from 1 to 10 mg / kg of body weight, for parenteral administration. The bipranole and its salts can be administered as conventional galenical preparations, in solid or liquid form, e.g. as tablets, coated tablets, capsules, powders in granules, dragees, suppositories or solutions. These are produced in a conventional manner. The active ingredient can be mixed with conventional adjuvants such as, tablet binders, fillers, preservatives, tablet disintegrating agents, emollient flow agents, surfactants, dispersing agents, emulsifiers, solvents, retarding agents and / or antioxidants; H. 8ucker et al., Phar mazeutische lechnologie, Thieme-Verlag, Òtuttgart 1978. 9 active ingredient in the resulting preparation varies between 1 and 99% by weight.

The examples illustrate the invention.

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Example 1

9.04 g (0.04 M) of o- (epoxy-2,3-propoxy) -diphenyl and 29.2 g (0.4%) of tert-butylamine were heated under reflux for 5 hours. The reaction mixture is then evaporated under reduced pressure. The residue is dissolved in 1N hydrochloric acid and the acidic solution is extracted with diethyl ether. The acid solution is then basified using a 137% sodium hydroxide solution. The separation oil is extracted with. diethyl ether. The ether extract is dried over sodium sulfate and eva. porate. The residue is distilled under reduced pressure. You get

8.1 g of tert-butylamino-3-ίphenyl-2 * -phenoxy) -1 propanol-2 with a boiling point of 151 to 156 ° 0 / 0.1 mbar.

hydrochloride is obtained by introducing hydrogen chloride gas into the solution of oipranole in diethyl ether.

Maintenance in the cold results in crystallization. The crystalline hydrochloride is filtered and dried in a desiccator. The product has a melting point of 123 to 124 ° C (in a closed melting point capillary tube).

Example 2

Preparation of tablets>

(a) Ingredients

Bipranole-KCl 75.00 cr O Microcrystalline cellulose (powder, 50 yxm) 15.75 ç O Poly- (l-vinyl-2-pyrrolidone) 5.00 cr O Hydroxypropylmethylcellulose 2910 'z ty j r c / g Magnesium bstereate 0.50 (ff V? 100.00 cr O

(b) Mixing and granulation

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4 *.

-8Ο bipranole-HGl is optionally sieved, all materials, except magnesium stearate, are mixed in a mixer where they are moistened with an appropriate amount of granulation liquid (e.g. water or 1: l isopropanol-dichloromethane).

The wet mixture is passed through a suitable sieve, dried in a drying chamber and sieved again. 3 dry granulate is mixed with the magnesium stearate in the mixer.

Claims (2)

V. - Method of preparing a pharmaceutical composition for the treatment of cardiac arrhythmias characterized by comprising mixing tert-butylamino-3-kphenyl-2'-phenoxy) -1-propanol-2 of the formula or their pharmacologically acid addition salts acceptable in an amount of approximately 60 mg to 4,303 mg per unit dose, with conventional pharmacologically acceptable diluents and / or auxiliary agents. 2§. - treatment method characterized in that it comprises administering orally or parenterally to a patient in need of said treatment, tert-butylamino-3-kphenyl-2'-phenoxy) -1-propanol-2 or its pharmacologically acceptable acid addition salts , in an amount of approximately 5 to 75 mg / kg of body weight, in oral administration, from 1 to 10 mg / kg of cornoral weight in parenteral administration.